BOSTON - March 19, 2008 - A study appearing in this week's
New England Journal of Medicine confirms that a combination
of gene variants previously associated with cholesterol levels does
reflect patients' LDL and HDL levels and can signify increased risk
of heart attack, stroke or sudden cardiac death. Led by researchers
from the Massachusetts General Hospital (MGH) Cardiology
Division, the study's findings are a first step towards the
ability to identify individuals who might benefit from earlier use
of cholesterol-lowering medications and other measures to combat
elevated risk.

"The prospect of personalized medicine has received much hype,
but until recently, there has been little hard evidence to support
the promise," says Sekar Kathiresan, MD, MGH Director of Preventive
Cardiology, the paper's lead author. "We feel that our
data provides two insights. First, we provide a foundation for the
possibility that a panel of gene variants will eventually be useful
in preventive cardiac care. Second, we show that the combination
of multiple variants related to cholesterol importantly contribute
to the genetic risk for heart attack."

It is estimated that about half the variation in high-density lipoprotein
(HDL) and low-density lipoprotein (LDL) cholesterol levels is inherited,
rather than being caused by lifestyle factors such as diet and exercise.
While studies have associated several gene variants with cholesterol
levels, exactly how those variants impact the risk of cardiovascular
disease is unclear. The current study was designed to explore the
influence of those variants on the risk of cardiovascular events
- heart attack, stroke or sudden cardiac death - and whether measuring
such variants could help predict risk better than simply measuring
HDL and LDL levels.

Since the effects of individual gene variants appears slight, the
research team looked at a combination of 9 single-nucleotide polymorphisms
(SNPs) previously associated with cholesterol levels. They analyzed
data from 5,414 Swedish adults who participated in a major prospective
epidemiological study and correlated data - including standard measurements
of HDL and LDL cholesterol and the presence of the 9 gene variants
- with information on the participants' subsequent medical histories
available from a registry of information collected on all Swedish
citizens. After the initial genotyping of participants not receiving
lipid-lowering therapy, participants were assigned a genotype score
ranging from 0 to 18, based on how many copies of the unfavorable
SNPs they carried. Of the participants who had no cardiovascular
events before enrolling in the study, 238 suffered a heart attack,
stroke or cardiac death during the subsequent 10.6 years.

Higher genotype scores did reflect higher LDL ("bad")
cholesterol and lower HDL ("good") cholesterol levels.
Importantly, those with genotype scores of 11 or higher had a 63
percent greater risk of a cardiovascular event than did those with
scores of 9 or lower. Although testing for the panel of 9 SNPs was
not better than standard risk factors for predicting cardiac events
in the overall population, among participants classified at intermediate
risk by standard measures, adding the 9-SNP panel significantly
improved the ability to distinguish truly elevated or reduced risk
levels.

"A current clinical dilemma is how early to start patients
on cholesterol-lowering medications like statins that can reduce
the risk of heart attack. Our data suggest that those individuals
classified as higher risk based on a genetic test may deserve more
intense pharmacological and lifestyle treatments," says Kathiresan.
"But before we can move from our pilot data to information
that can impact the care of patients with or at risk for cardiovascular
disease, we need to discover all the risk-related variants - and
there will probably be 50 to 100 - and then conduct clinical studies
confirming that this information can reliably guide patient care."
Earlier this year Kathiresan, an instructor in Medicine at Harvard
Medical School, and colleagues from the Broad Institute of Massachusetts
Institute of Technology and Harvard University began this gene-discovery
process and identified six new cholesterol-associated gene variants
in a separate study published in Nature Genetics.

Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.